Programmed cell death (PCD) is mediated by a process called apoptosis. Although the investigation of cell death is a relatively new field of study, it has become readily apparent that many disease states are manifested due to the aberrant control of programmed cell death. Recent evidence suggest that the failure of cells to undergo apoptotic cell death might be involved in the pathogenesis of a variety of human diseases including cancer, autoimmune diseases and viral infections. The understanding of survival pathways would be critical in disease states where excessive cell numbers, such as in various cancers, are the result of cell survival signals preventing cell death rater than the result of uncontrolled proliferation. It is known that a number of peptide factors including the neurotrophins, Insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), and epidermal growth factor (EGF) promote cell survival by suppressing the intrinsic cell death program. The growth factors listed above bind to and activate their respective receptor tyrosine kinases (RTK) at the cell surface which, in turn, stimulate the anti-apoptotic activity of the proto-oncogene ras. Ras controls the activity of a number of effector pathways, two of which result in activation of protein kinases known to mediate its anti-apoptotic effect: the mitogen activated protein kinase p42p44 (MAPK) of the ERK-type (extracellular signal-related kinase) via Raf and the Akt kinase via phosphoinositide 3-kinase (PIK-3). Mutational activation of ras oncogenes is associated with about 30% of all human tumors, potentially suppressing the ability of the body to remove the cancerous cell.
The product of the gene hid is responsible for inducing apoptosis in drosophila embryos as well as transfected insect and mammalian cells. When ectopically expressed, Hid induces apoptosis by activating a caspase protease pathway. In the absence of Hid function many cells that should die fail to do so. Unlike other cell death activating genes (e.g. reaper and grim), hid is expressed in many cells that are not destined to undergo apoptosis. This observation suggests that efficient post-translational survival mechanisms operate in these cells to protect them from Hid-induced apoptosis. Activation of the Ras/MAPK pathway in transfected cells has been shown to decrease or inhibit Hid-induced cell death.
The screening of potential therapeutics has been hindered by both a lack of understanding of the physiological basis of cell death and by a dearth of reagents specific for critical points in the cell death signaling pathways. Additionally, much work has focused on the delineation of the death-inducing pathway and reagents that may block it and not on pathways that confer survival signals. What is needed are reagents and methodologies that allow for the identification and testing of agonists and antagonists of cell survival pathways.